US6572879B1 - Formulations for transdermal delivery of pergolide - Google Patents

Formulations for transdermal delivery of pergolide Download PDF

Info

Publication number
US6572879B1
US6572879B1 US08/473,631 US47363195A US6572879B1 US 6572879 B1 US6572879 B1 US 6572879B1 US 47363195 A US47363195 A US 47363195A US 6572879 B1 US6572879 B1 US 6572879B1
Authority
US
United States
Prior art keywords
pergolide
reservoir
therapeutically effective
membrane
permeation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US08/473,631
Other languages
English (en)
Inventor
Su Il Yum
Melinda K. Nelson
Patricia S. Campbell
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Alza Corp
Original Assignee
Alza Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Alza Corp filed Critical Alza Corp
Priority to US08/473,631 priority Critical patent/US6572879B1/en
Assigned to ALZA CORPORATION reassignment ALZA CORPORATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: YUM, SU IL, CAMPBELL, PATRICIA S., NELSON, MELINDA K.
Assigned to ALZA CORPORATION reassignment ALZA CORPORATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: YUM, SU IL, NELSON, MELINDA K., CAMPBELL, PATRICIA S.
Priority to AT95929346T priority patent/ATE361073T1/de
Priority to DE69637061T priority patent/DE69637061T2/de
Priority to DE19681435T priority patent/DE19681435T1/de
Priority to EP95929346A priority patent/EP0831827B1/de
Priority to JP9501953A priority patent/JPH11507361A/ja
Priority to EP04075596A priority patent/EP1428527A1/de
Priority to PCT/US1996/009692 priority patent/WO1996040139A1/en
Priority to GB9724267A priority patent/GB2316004B/en
Priority to AU64764/96A priority patent/AU6476496A/en
Priority to PT95929346T priority patent/PT831827E/pt
Priority to CA002221263A priority patent/CA2221263A1/en
Priority to ES95929346T priority patent/ES2285704T3/es
Priority to DK95929346T priority patent/DK0831827T3/da
Priority to US08/768,600 priority patent/US6001390A/en
Priority to MXPA/A/1997/009872A priority patent/MXPA97009872A/xx
Priority to US10/121,478 priority patent/US20040209909A1/en
Publication of US6572879B1 publication Critical patent/US6572879B1/en
Application granted granted Critical
Priority to JP2007168802A priority patent/JP2007238636A/ja
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/48—Ergoline derivatives, e.g. lysergic acid, ergotamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7084—Transdermal patches having a drug layer or reservoir, and one or more separate drug-free skin-adhesive layers, e.g. between drug reservoir and skin, or surrounding the drug reservoir; Liquid-filled reservoir patches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids

Definitions

  • This invention relates to the safe and efficacious transdermal administration of pergolide for, among other things, the treatment of Parkinson's Disease. More particularly, the invention relates to novel methods, compositions, and devices for administering pergolide to a subject through a body surface or membrane over a sustained time period.
  • Pergolide 8-[(methylthio)methyl]-6-propylergoline, a compound based on the ergoline ring system, is reported to be a dopaminergic agonist that also decreases plasma prolactin concentrations. When used for treating Parkinson's Disease, pergolide is used as an adjuvant to levodopa.
  • the composition may be delivered orally, sublingually, parenterally, percutaneously or nasally.
  • the dopaminergic agonist effect of pergolide has resulted in its use in a variety of treatments, in addition to the treatment of Parkinson's Disease.
  • U.S. Pat. No. 4,800,204 discusses a method of controlling tobacco use by orally or parenterally administering a direct dopamine receptor agonist such as pergolide.
  • the oral administration of pergolide in the treatment of Parkinson's Disease is initiated with 0.05 mg/day dosage for the first 2 days.
  • the dosage is then gradually increased by 0.1 or 0.15 mg/day every third day over the next 12 days of therapy.
  • the dosage may-then be increased by 0.25 mg/day every third day until an optimum therapeutic dosage is achieved at a range of about 1.5 to 8.0 mg/day.
  • the daily dose is divided into three oral doses.
  • the side effects of oral administration include, but are not limited to nausea, vomiting, dizziness and orthostatic hypotension.
  • the transdermal route of administration appeared to offer many advantages, particularly with respect to agents that had short half lives and therefore required frequent, repeated dosing or were subject to a high degree of first-pass metabolism by the liver when orally administered.
  • the peaks and valleys in blood concentration resulting of frequent periodic doses of short half-life agents would be eliminated and replaced by substantially constant plasma concentration. This would not only improve patient compliance but also would eliminate the alternating periods of high side-effects and ineffective blood concentrations associated with period dosing. It was also thought that administering the agent through the skin directly into the blood stream would eliminate first-pass metabolism of orally administered agents.
  • transdermal route of administration rather than being available to every short half-life agent of high potency and skin permeability, was found to be available only to those few agents that possess the proper combination of a host of characteristics, most of which are unpredictable, required to render the agent suitable for safe and effective transdermal administration.
  • the permeability of the skin to the agent must be sufficiently high so that the agent can be administered at a therapeutically effective rate through an area of skin no greater than about 200 cm 2 and preferably no greater than 50 cm 2 .
  • the person-to-person variation in skin permeability at similar sites should also be considered.
  • the skin beneath the transdermal delivery device has the capability of binding or dissolving a certain amount of agent.
  • the amount of agent so bound must be supplied to the skin before the agent can be delivered into the blood stream at therapeutically effective rates. If large amounts of the agent are bound in the skin, significant delays in the onset of therapeutic effect (“lag time”) will be observed together with corresponding delays and termination of effect upon removal of the device. The potential also exists for toxic quantities of potent agents to be contained within the skin beneath the device.
  • Skin binding is not related to skin permeability. Agents that are highly permeable may also be highly bound causing a lag time sufficiently long as to render them unsuitable for their intended use.
  • Irritation The skin reacts to many topically applied substances, particularly those maintained under occlusion, by blistering or reddening accompanied by unpleasant burning, itching, and stinging sensations. Animal models are used to screen for irritation. Animal models, however, often produce both false positives and false negatives. There is also a wide interpersonal variation in susceptibility to irritation. An agent must be minimally irritating in a large percentage of the potential patient population in order to be suitable for safe and effective transdermal administration.
  • Sensitization is an allergic reaction which is induced when an agent is first applied to the skin and is elicited upon continued exposure which may occur immediately or after a long period of seemingly harmless exposure.
  • the sensitization may be local, elicited by topical exposure, which manifests itself as contact dermatitis accompanied by blistering, itching, reddening and burning at the site of application. More seriously, the sensitization may be systemic, elicited by topical application but manifesting itself by more general allergic reactions at sites other than the site of application. Most seriously, the systemic sensitization may be elicited by oral or intravenous administration of the drug. If the latter occurs, the patient will be unable to take the drug by any route of administration.
  • the half-life of an agent is the time after administration that half of the amount administered has been eliminated from the body. Because blood concentrations of continuously administered agents will continue to increase for approximately five half-lives before steady-state constant blood concentrations are achieved, an agent must have a relatively short half-life to be suitable for continuous transdermal administration. The transdermal half-lives of most agents have not been determined. When half-lives of agents determined from intravenous administration are compared with half-lives determined from transdermal administration, the transdermal half-lives are generally longer but there can be wide variation in half-life between individuals based upon factors such as age, sex, health, and body type.
  • Constant blood levels may not produce the desired therapeutic effects. For example, a therapeutic effect may only be observed at peak blood concentration obtained from bolus dosing but the peak concentration cannot be maintained because of side effects associated therewith. Also, continuous administration of many agents produces tolerance that may require either some agent-free interval or continually increasing and therefore potentially hazardous doses of the agent.
  • Potency Although a certain degree of potency is required for transdermally administered agent to be effective, it is also possible for an agent to be too potent. As potency increases, lower blood concentrations are required and much smaller quantities are administered. Because of normal inter-individual variations and skin permeability, it may not be possible to precisely control whether a patient is receiving 1 ⁇ g/hr or 2 ⁇ g/hr, for example. For a highly potent agent, a 1 ⁇ g/hr administration may be totally ineffective and a 2 ⁇ g/hr rate fatal. Thus, the therapeutic index of an agent, which is the ratio of toxic blood concentration to the therapeutic blood concentration, becomes extremely significant. A highly potent agent may also need to have a relatively high therapeutic index in order to be suitable for transdermal administration.
  • pergolide would be delivered through the skin at meaningful therapeutic rates either as a base or salt because, as its chemical name 8-[(methylthiolmethyl]6-propylergoline monomethanesulfonate)] indicates, it has a complex chemical structure which does not lend itself to readily permeate through biological membranes such as the skin.
  • pergolide can be safely and efficaciously administered transdermally to provide, among other things, treatment for Parkinson's Disease, with a reduced incidence of side effects and improved patient compliance.
  • the present invention provides methods for the transdermal delivery of pergolide and delivery systems for effecting the same, which are suitable for the administration of pergolide continuously through a body surface or membrane to achieve and maintain therapeutic blood plasma levels of pergolide in a patient.
  • a particularly advantageous aspect of this invention is the ability to maintain substantially constant blood plasma levels of pergolide in a patient over extended periods of time.
  • transdermal intends both percutaneous and transmucosal administration, ie, passage of pergolide through intact unbroken skin or mucosal tissue into the systemic circulation.
  • pergolide intends not only the basic form of pergolide but also a pharmaceutically acceptable salt form of pergolide.
  • salt intends, but is not limited to, pharmaceutically acceptable salts such as chlorides, acetates, sulfates, phosphates, mesylates.
  • pergolide therapy intends all medical conditions for which pergolide is or will be indicated, including, without limitation, as a psychic energizer and in the treatment of Parkinson's Disease, migraine, allergic responses, urticaria, hypertension, endometritis, and other conditions associated with dopaminergic agonists.
  • the term “individual” intends a living mammal and includes, without limitation, humans and other primates, livestock and sports animals such as cattle, pigs and horses, and pets such as cats and dogs.
  • the term “therapeutic effective amount” intends the dose of pergolide that provides pergolide therapy, in the case of adult humans, the optimum dosage range is normally about 1.5 to 8 mg of pergolide per day.
  • sustained time period or “administration period” intends at least about 8 hours and will typically intend a period in the range of about one to about seven days.
  • predetermined area of skin intends a defined area of intact unbroken skin or mucosal tissue. That area will usually be in the range of about 5 cm 2 to about 100 cm 2 .
  • permeation enhancement intends an increase in the permeability of skin to pergolide in the presence of a permeation enhancer as compared to permeability of skin to pergolide in the absence of a permeation enhancer.
  • the present invention relates to improved compositions, devices and methods for the transdermal administration of pergolide in the treatment of Parkinson's Disease, among other things.
  • pergolide may be safely and efficaciously administered transdermally through a body surface or membrane at a therapeutically effective rate for a predetermined, sustained time period in order to provide an effective therapeutic result.
  • Another aspect of the present invention is directed to the transdermal administration of pergolide together with a suitable permeation enhancer or mixture of enhancers.
  • Therapeutic blood plasma levels of pergolide in a patient of about 100-2000 pg/ml may be achieved and maintained by the practice of this invention.
  • the system of the invention comprises a carrier or matrix adapted to be placed in pergolide or pergolide- and permeation-enhancing mixture-transmitting relation to the selected skin or other body site.
  • the carrier or matrix contains sufficient amounts of pergolide or any acceptable pharmaceutical salt thereof to continuously administer to the site, over a predetermined delivery period, pergolide, at a therapeutically effective rate.
  • the carrier or matrix contains sufficient amounts of pergolide or any acceptable pharmaceutical salt thereof and the permeation-enhancing mixture to continuously coadminister to the site, over a predetermined delivery period, pergolide, at a therapeutically effective rate, and a permeation enhancer or permeation enhancer mixture.
  • FIG. 1 is a cross-section through a schematic perspective view of one embodiment of a transdermal therapeutic system according to this invention prior to application to the skin.
  • FIG. 2 is a cross-section view through another embodiment of this invention.
  • FIG. 3 is a cross-section view through another embodiment of this invention.
  • FIG. 4 is a cross-section view through another embodiment of this invention.
  • FIG. 5 is a graph of the flux of pergolide base through human epidermis, in vitro, at 35° C., from various aqueous and non-aqueous donors.
  • FIG. 6 is a graph of the flux of pergolide mesylate through human epidermis, in vitro, at 35° C., from various aqueous and non-aqueous donors.
  • FIG. 7 is a graph of the cumulative release of pergolide base through human epidermis at 35° C., in vitro from an EVA matrix system with various permeation enhancers.
  • FIG. 8 is a graph of the cumulative release of pergolide mesylate through human epidermis at 35° C., in vitro, from an EVA matrix system with various permeation enhancers.
  • FIG. 9 is a graph of the cumulative release of pergolide base through human epidermis at 35° C. in vitro, from an EVA matrix system with various permeation enhancers.
  • FIG. 10 is a graph of the cumulative release of pergolide mesylate through human epidermis at 35° C., in vitro, from an EVA matrix system with various permeation enhancers.
  • FIG. 11 is a graph of the cumulative release of pergolide base through human epidermis in vitro at 35° C., from an EtOH system having an 18% EVA rate controlling membrane with various permeation enhancers and a polyisobutylene/mineral oil based in-line contact adhesive preloaded with drug.
  • FIG. 12 is a graph of the cumulative release of pergolide mesylate through human epidermis, in vitro, at 35° C., from an EtOH system having an 18% EVA rate controlling membrane with various permeation enhancers and a polyisobutylene/mineral oil based in-line contact adhesive preloaded with drug.
  • FIG. 13 is a graph of the cumulative release of pergolide base through human epidermis, in vitro, at 35° C., from an EtOH system having a 28% EVA rate controlling membrane with various permeation enhancers.
  • FIG. 14 is a graph of the cumulative release of pergolide mesylate through human epidermis, in vitro, at 35° C., from an EtOH system having a 28% EVA rate controlling membrane with various permeation enhancers.
  • FIG. 15 is a graph of the flux of pergolide base through human epidermis, in vitro, at 35° C., from an EtOH system having a 28% EVA rate controlling membrane with various permeation enhancers and a polyisobutylene/mineral oil based in-line contact adhesive preloaded with drug.
  • FIG. 16 is a graph of the flux of pergolide mesylate through human epidermis, in vitro, at 35° C., from an EtOH system having a 28% EVA rate controlling membrane with various permeation enhancers and a polyisobutylene/mineral oil based in-line contact adhesive preloaded with drug.
  • FIG. 17 is a graph of the flux of pergolide mesylate through human epidermis, in vitro, at 35° C., from an Laureth-4/GML/EVA 40 system with and without various in-line adhesives.
  • FIG. 18 is a graph of the flux of pergolide mesylate through human epidermis, in vitro, at 35° C., from an Laureth-4/GML/EVA 40/Mineral Oil system with and without various in-line adhesives.
  • FIG. 19 is a graph of the cumulative release of pergolide mesylate through human epidermis, in vitro, at 35° C., from an Laureth-4/GML/EVA 40/Mineral Oil system with and without various in-line adhesives.
  • FIG. 20 is a graph of the cumulative release of pergolide mesylate through human epidermis, in vitro, at 35° C., from an Laureth-4/GML/EVA 40 system with and without various in-line adhesives.
  • pergolide may be administered to the human body at a therapeutically effective rate via the transdermal route for the purpose of treating Parkinson's Disease, among other things, when administered alone or coadministered with a suitable permeation enhancer or enhancer mixture.
  • the plasma terminal half-life of pergolide administered transdermally is in the range of 5 to 10 hours, and therapeutic blood plasma levels of 100 pg/ml to 2000 pg/ml can be achieved from administration rates in the range of 30 ⁇ g/hr to 150 ⁇ g/hr.
  • Representative in vitro skin fluxes of pergolide through human skin are in the. range of 0.1 ⁇ g/cm 2 ⁇ hr to 8.0 ⁇ g/cm 2 ⁇ hr, depending on the form of pergolide (base or salt) and the permeation enhancer or enhancer mixture.
  • Therapeutic blood plasma levels can be achieved within approximately 5 to 10 hours following application of the first patch, and steady state blood plasma concentrations are preferably maintained at about 300-1200 pg/ml with subsequent system applications.
  • a subsequent system is applied, a lag period of no pergolide delivery is not experienced due to the presence of a skin depot of pergolide remaining from the prior system, thus pergolide is continuously administered throughout subsequent system applications in order to maintain therapeutic blood plasma levels of pergolide over a sustained time period.
  • the range of desired and achievable cumulative release of pergolide, arriving through the skin at a limited area is 1.5-8.0 mg per 24 hours.
  • the system is easily adapted to provide a cumulative release of pergolide over a 24 hour period of less than 1.5 mg if necessary. Additionally, the system is easily adapted for shorter or longer duration treatments, but generally 72 hours is the preferred duration for a single treatment.
  • a 2% by weight pergolide6mesylate/water formulation has an average baseline skin flux of about 1.1 ⁇ g/cm 2 ⁇ hr over a 50 hour period, thus requiring a permeation increase of at least 3 ⁇ in order to achieve this minimum desired dosage from a 20 cm 2 system. Accordingly, there is a need to increase the pergolide skin flux.
  • the desired pergolide admininstration rate may be achieved by increasing the surface area of the transdermal delivery device without increasing the flux.
  • the surface area of a patch would have to be increased to about 60 cm 2 in order to deliver approximately 1.6 mg of pergolide over a 24 hour period.
  • permeation enhancers include, but are not limited to: monoglycerides such as glycerol monolaurate, glycerol monooleate or glycerol monolinoleate, lactate esters such as lauryl lactate, caproyl lactic acid, lauramide diethanolamine (LDEA), mineral oil, dimethyl lauramide, polyethylene glycol-4 lauryl ether (Laureth-4), and ethanol, alone or in combinations of one or more.
  • LDEA lauramide diethanolamine
  • An embodiment of this invention also relates to codelivery of at least one of the permeation enhancers mentioned above to aid in the transdermal delivery of pergolide.
  • the present inventors also found that certain adhesives were preferred as the in-line contact adhesive when one was used in a therapeutic transdermal pergolide system. More particularly, it was found that systems using polyisobutylene adhesives as the in-line contact adhesive resulted in greater flux of pergolide through skin than when other adhesives, such as acrylate adhesives, were used.
  • the present invention in one embodiment, is directed to a composition of matter for administration to a body surface or membrane to deliver pergolide by permeation through the body surface or membrane at a therapeutically effective rate, wherein the composition comprises an amount of pergolide in a carrier effective to permit sustained release of pergolide at a therapeutically effective rate over an administration period of at least about 8 hours, wherein said therapeutically effective rate of pergolide release achieves therapeutic blood plasma levels of pergolide in a patient over a substantial portion of said administration period.
  • compositions of matter for administration to a body surface or membrane to deliver pergolide by permeation through the body surface or membrane at a therapeutically effective rate, wherein the composition comprises, in combination:
  • a permeation-enhancing amount of a permeation enhancer or mixture of permeation enhancers may be present in the composition in an amount ranging from 0.1 to 20% by weight.
  • pergolide, or pergolide and permeation enhancer or enhancer mixture are placed in drug or drug and permeation-enhancing mixture-transmitting relationship to an appropriate body surface, preferably in a pharmaceutically acceptable carrier thereof, and maintained in place for the desired period of time.
  • the pergolide and the permeation enhancer or mixture are typically dispersed within a physiologically compatible matrix or carrier, as more fully described below, which may be applied directly to the body as an ointment, gel, cream, suppository or sublingual or buccal tablet.
  • a physiologically compatible matrix or carrier such as a physiologically compatible matrix or carrier, as more fully described below, which may be applied directly to the body as an ointment, gel, cream, suppository or sublingual or buccal tablet.
  • a physiologically compatible matrix or carrier such as more fully described below, which may be applied directly to the body as an ointment, gel, cream, suppository or sublingual or buccal tablet.
  • Such compositions can also contain other permeation enhancers, stabilizers, dyes, diluents, pigments, vehicles, inert fillers, excipients, gelling agents, vasoconstrictors, and other components of topical compositions as are known to the art.
  • the pergolide or pergolide and permeation enhancer or mixture would be administered from a transdermal device as more fully described below.
  • transdermal delivery devices Examples of suitable transdermal delivery devices are illustrated in FIGS. 1, 2 , 3 and 4 .
  • the same reference numbers are used throughout the different figures to designate the same or similar components. The figures are not drawn to scale.
  • a preferred embodiment of a transdermal therapeutic system comprises transdermal delivery device 10 comprising a reservoir 12 containing pergolide or a pharmaceutically acceptable salt. Reservoir 12 would also contain the permeation-enhancing compound or mixture, if used. Reservoir 12 is preferably in the form of a matrix containing pergolide or pergolide and the permeation enhancer or enhancer mixture dispersed therein. Reservoir 12 is sandwiched between a backing 14 and an in-line contact adhesive layer 16 . The device 10 adheres to the surface of the skin 18 by means of the adhesive layer 16 . The adhesive layer 16 may optionally contain the permeation-enhancing compound and/or pergolide. A strippable release liner (not shown in FIG.
  • a rate-controlling membrane (not shown) may be present between the reservoir 12 and the adhesive layer 16 .
  • a rate-controlling membrane (not shown) may be present between the reservoir 12 and the adhesive layer 16 .
  • the preferred embodiments of this invention utilize an in-line adhesive as is shown in FIG. 1, other means for maintaining the system on the skin can be employed. Such means include a peripheral ring of adhesive outside the path of the drug from the system to the skin or the use of other fastening means such as buckles, belts, and elastic arm bands.
  • transdermal therapeutic device 20 may be attached to the skin or mucosa of a patient by means of an adhesive overlay 22 .
  • Device 20 is comprised of reservoir 12 containing pergolide or a pharmaceutically acceptable salt and a permeation-enhancing compound or mixture, if used.
  • Reservoir 12 is preferably in the form of a matrix containing the pergolide or pergolide and permeation enhancing compound dispersed therein.
  • a backing layer 14 is provided adjacent one surface of reservoir 12 .
  • Adhesive overlay 22 maintains the device on the skin and may be fabricated together with, or provided separately from, the remaining elements of the device. With certain formulations, the adhesive overlay 22 may be preferable to the in-line contact adhesive 16 as shown in FIG. 1 .
  • Backing layer 14 is preferably slightly larger than reservoir 12 , and in this manner prevents the materials in reservoir 12 from adversely interacting with the adhesive in overlay 22 .
  • a rate-controlling membrane (not shown in FIG. 2) may be provided on the skin-proximal side of reservoir 12 .
  • a strippable release liner 24 is also provided with device 20 and is removed just prior to application of device 20 to the skin.
  • transdermal delivery device 30 comprises a pergolide and permeation-enhancing compound-containing reservoir (“pergolide reservoir”) 12 substantially as described with respect to FIG. 1 .
  • Permeation enhancer reservoir (“enhancer reservoir”) 26 comprises the permeation-enhancing compound or mixture dispersed throughout and contains pergolide at or below saturation, when in equilibrium with the first reservoir.
  • Enhancer reservoir 26 is preferably made from substantially the same matrix as is used to form pergolide reservoir 12 .
  • a rate-controlling membrane 28 for controlling the release rate of the permeation enhancer from enhancer reservoir 26 to pergolide reservoir 12 is placed between the two reservoirs.
  • a rate-controlling membrane (not shown in FIG. 3) for controlling the release rate of the enhancer from pergolide reservoir 12 to the skin may also optionally be utilized and would be present between adhesive layer 16 and reservoir 12 .
  • the rate-controlling membrane may be fabricated from permeable, semipermeable or microporous materials which are known in the art to control the rate of agents into and out of delivery devices and having a permeability to the permeation enhancer lower than that of drug reservoir 12 .
  • Suitable materials include, but are not limited to, polyethylene, polyvinyl acetate, ethylene n-butyl acetate and ethylene vinyl acetate copolymers.
  • a backing 14 Superimposed over the permeation enhancer reservoir 26 of device 30 is a backing 14 .
  • an adhesive layer 16 On the skin-proximal side of reservoir 12 are an adhesive layer 16 and a strippable liner 24 which would be removed prior to application of the device 30 to the skin.
  • the carrier or matrix material of the reservoirs has sufficient viscosity to maintain its shape without oozing or flowing. If, however, the matrix or carrier is a low-viscosity flowable material such as a liquid or a gel, the composition can be fully enclosed in a pouch or pocket, as known to the art from U.S. Pat. No. 4,379,454 (noted above), for example, and as illustrated in FIG. 4 .
  • Device 40 shown in FIG. 4 comprises a backing member 14 which serves as a protective cover for the device, imparts structural support, and substantially keeps components in device 40 from escaping the device.
  • Device 40 also includes reservoir 12 , which contains the pergolide or pergolide and permeation-enhancer compound, and bears on its surface distant from backing member 14 , a rate-controlling membrane 28 for controlling the release of pergolide and/or permeation-enhancing compound from device 40 .
  • the outer edges of backing member 14 overlay the edges of reservoir 12 and are joined along the perimeter with the outer edges of the rate-controlling membrane 28 in a fluid-tight arrangement.
  • This sealed reservoir may be effected by pressure, fusion, adhesion, an adhesive applied to the edges, or other methods known in the art. In this manner, reservoir 12 is contained wholly between backing member 14 and rate-controlling membrane 28 .
  • On the skin-proximal side of rate-controlling membrane 28 are an adhesive layer 16 and a strippable liner 24 which would be removed prior to application of the device 40 to the skin.
  • reservoir 12 contains the permeation-enhancing compound and contains pergolide at or below saturation.
  • the pergolide and an additional amount of permeation-enhancing mixture are present in adhesive layer 16 , which acts as a separate reservoir.
  • the pergolide with or without the permeation-enhancing mixture can be administered to human skin or mucosa by direct application to the skin or mucosa in the form of an ointment, gel, cream or lotion, for example, but are preferably administered from a skin patch or other known transdermal delivery device which contains a saturated or unsaturated formulation of the pergolide or pergolide and enhancer.
  • the formulation may be aqueous or non-aqueous based.
  • the formulation should be designed to deliver the pergolide or the pergolide and the permeation-enhancing mixture at the necessary fluxes.
  • Aqueous formulations typically comprise water or water/ethanol and about 1-5 wt % of a gelling agent, an example being a hydrophilic polymer such as hydroxyethylcellulose or hydroxypropylcellulose.
  • Typical non-aqueous gels are comprised of silicone fluid or mineral oil.
  • Mineral oil-based gels also typically contain 1-2 wt % of a gelling agent such as colloidal silicon dioxide. The suitability of a particular gel depends upon the compatibility of its constituents with the drug and the permeation-enhancing mixture, if used, in addition to any other components in the formulation.
  • the reservoir matrix should be compatible with pergolide, the permeation enhancer, and any carrier therefor.
  • matrix refers to a well-mixed composite of ingredients fixed into shape.
  • the reservoir matrix is preferably a hydrophilic polymer, eg, a hydrogel.
  • the reservoir matrix is preferably composed of a hydrophobic polymer.
  • Suitable polymeric matrices are well known in the transdermal drug delivery art, and examples are listed in the above-named patents previously incorporated herein by reference.
  • a typical laminated system would consist essentially of a polymeric membrane and/or matrix such as ethylene vinyl acetate (EVA) copolymers, such as those described in U.S. Pat. No. 4,144,317, preferably having a vinyl acetate (VA) content in the range of from about 9% up to about 60% and more preferably about 9% to 40% VA.
  • EVA ethylene vinyl acetate
  • Polyisobutylene/oil polymers containing from 4-25% high molecular weight polyisobutylene and 20-81% low molecular weight polyisobutylene with the balance being an oil such as mineral oil or polyisobutynes may also be used as the matrix material.
  • the amount of pergolide present in the therapeutic device and required to achieve an effective therapeutic result depends on many factors, such as the minimum necessary dosage of the pergolide for the particular indication being treated; the solubility and permeability of the matrix, taking into account the presence of a permeation enhancer, of the adhesive layer and of the rate-controlling membrane, if present; and the period of time for which the device will be fixed to the skin.
  • the minimum amount of pergolide is determined by the requirement that sufficient quantities of pergolide must be present in the device to maintain the desired rate of release over the given period of application.
  • the maximum amount for safety purposes is determined by the requirement that the quantity of pergolide present cannot exceed a rate of release that reaches toxic levels.
  • the pergolide is normally present in the matrix or carrier at a concentration in excess of saturation, the amount of excess being a function of the desired length of the delivery period of the system.
  • Pergolide may, however, be present at a level below saturation without departing from this invention as long as it is continuously administered to the skin or mucosal site at a therapeutic rate and for a period of time sufficient to deliver a therapeutically effective amount of pergolide that provides the desired therapeutic result.
  • the permeation enhancer useful in the present invention is selected from those compounds which are compatible with pergolide or its pharmaceutically acceptable salt and which provide enhanced skin permeation to the drug when it is administered together with the drug to the skin of a user. Additionally, the permeation enhancer must not adversely interact with the adhesive of the in-line contact adhesive layer if one is present.
  • Such permeation enhancers can be selected from, but are not limited to, C 2-4 alcohols such as ethanol and isopropanol, polyethylene glycol monolaurate, laureth-4, lauryl lactate, dimethyl lauramide, LDEA, caproyl lactic acid, mineral oil, esters of fatty acids having from about 10 to about 20 carbon atoms, and monoglycerides or mixtures of monoglycerides of fatty acids alone, or in combinations with each other.
  • C 2-4 alcohols such as ethanol and isopropanol
  • polyethylene glycol monolaurate such as laureth-4, lauryl lactate, dimethyl lauramide, LDEA, caproyl lactic acid, mineral oil, esters of fatty acids having from about 10 to about 20 carbon atoms, and monoglycerides or mixtures of monoglycerides of fatty acids alone, or in combinations with each other.
  • monoglycerides have been available as a mixture of monoglycerides of fatty acids with one monoglyceride being the principal component, from which component the mixture derives its name.
  • one commercial monoglyceride is Emerest 2421 glycerol monooleate (Emery Division, Quantum Chemical Corp.), which is a mixture of glycerol oleates with a glycerol monooleate content of 58% and a total monoesters content of 58%.
  • the monoglycerides are Myverol 1899K glycerol monooleate (Eastman Chemical Products) which has a glycerol monooleate content of 61% and a total monoesters content of 93%, and Myverol 1892K glycerol monolinoleate which has a glycerol monolinoleate content of 68% and a minimum total monoesters content of 90%.
  • the monoesters are chosen from those with from 10 to 20 carbon atoms.
  • the fatty acids may be saturated or unsaturated and include, for example, lauric acid, myristic acid, stearic acid, oleic acid, linoleic acid and palmitic acid.
  • Monoglyceride permeation enhancers include glycerol monooleate, glycerol monolaurate and glycerol monolinoleate, for example.
  • the permeation enhancer is a monoglyceride or a mixture of monoglycerides of unsaturated fatty acids, and more preferred is glycerol monolaurate (GML) with lauryl lactate or laureth-4.
  • GML glycerol monolaurate
  • the term “monoglyceride” refers to a monoglyceride or a mixture of monoglycerides of fatty acids.
  • glycerol monooleate having a total monoesters content of less than about 65% interacts adversely with known adhesive materials to such an extent that the adhesive cannot function to maintain a delivery device on the skin. Therefore, when an in-line adhesive is present as a part of the device of the invention so that a permeation enhancer must pass through the adhesive, and when glycerol monooleate is utilized as the permeation enhancer, the glycerol monooleate must have a total monoesters content of at least 65%.
  • the permeation-enhancing mixture is dispersed through the matrix or carrier, preferably at a concentration sufficient to provide permeation-enhancing amounts of enhancer in the reservoir throughout the anticipated administration period. Where there is an additional, separate permeation enhancer matrix layer as well, as in FIGS. 3 and 4, the permeation enhancer normally is present in the separate reservoir in excess of saturation.
  • the matrix or carrier may also contain dyes, pigments, inert fillers, excipients and other conventional components of pharmaceutical products or transdermal devices known to the art.
  • the pergolide, or pergolide and permeation-enhancing compound be administered from a rate-controlled transdermal delivery device.
  • Rate control can be obtained either through a rate-controlling membrane or adhesive or both as well as through the other means.
  • a certain amount of pergolide will bind reversibly to the skin, and it is accordingly preferred that the skin-contacting layer of the device include this amount of pergolide as a loading dose.
  • the surface area of the device of this invention can vary from about 1-200 cm 2 .
  • a typical device will have a surface area within the range of about 5-50 cm 2 , preferably about 20 cm 2 .
  • the devices of this invention can be designed to effectively deliver pergolide for an extended time period of from several hours up to 7 days or longer. Seven days is generally the maximum time limit for application of a single device because the adverse affect of occlusion of a skin site increases with time and the normal cycle of sloughing and replacement of the skin cells occurs in about 7 days.
  • the transdermal drug delivery device contains sufficient amounts of permeation-enhancing compound as described above and of pergolide, in combination, to provide systemic administration of pergolide through the skin at a therapeutically effective rate and for a predetermined period of time for the pergolide to provide an effective therapeutic result.
  • a device for the transdermal administration of pergolide, at a therapeutically effective rate comprises:
  • (c) means for maintaining the reservoir in drug- and permeation-enhancing mixture-transmitting relation with the skin.
  • a device for the transdermal administration of pergolide, at a therapeutically effective rate comprises:
  • (c) means for maintaining the reservoir in drug- and permeation-enhancing mixture-transmitting relation with the skin.
  • a device for the transdermal administration of pergolide, at a therapeutically effective rate comprises:
  • (c) means for maintaining the reservoir in drug- and permeation-enhancing mixture-transmitting relation with the skin.
  • the backing may be a breathable or occlusive material such as polyethylene, polyurethane, polyester or ethylene vinyl acetate films.
  • An occlusive Medpar® backing is preferred. If an ethylene vinyl acetate is employed as the backing, preferably, it has an acetate content of 33% or 40%.
  • the means for maintaining the reservoir in drug and permeation-enhancing mixture transmitting relation with the skin are preferably a polyisobutylene adhesive, as described in the Examples that follow.
  • a further embodiment of the invention is directed to including in the adhesive a small percentage, eg, from about 2.5 to about 5 wt % of the pergolide or pharmaceutically acceptable salt.
  • the invention is also directed to a method of continuously administering pergolide to a patient at a therapeutically effective rate over an administration period in order to provide substantially constant therapeutically effective blood plasma levels of pergolide in a patient throughout a substantial portion of said administration period.
  • Therapeutic blood plasma levels of pergolide in a patient may be preferably maintained at about 100-2000 pg/ml, more preferably at about 300-1200 pg/ml.
  • Another method of the present invention is directed to a method for the transdermal coadministration of pergolide at a therapeutically effective rate together with a skin permeation-enhancing amount of a permeation enhancer or enhancer mixture in order to achieve and maintain therapeutic blood levels of pergolide in a patient, comprising:
  • pergolide is delivered at a therapeutically effective rate during a predetermined time period in order to achieve and maintain therapeutic blood levels of pergolide in a patient.
  • the pergolide and permeation-enhancing compound or mixture may be administered to the body surface or membrane by means of the devices and compositions described above.
  • a preferred embodiment of the present invention comprises a method of treating Parkinson's Disease.
  • pergolide should be present in plasma at concentrations above about 100 pg/mi, preferably at concentrations above about 300 pg/ml and most preferably at concentrations of about 1000 pg/ml.
  • pergolide is delivered at a therapeutic rate of at least about 100 ⁇ g per hour, but typically of at least 125 ⁇ g/hr, and more typically at about 150 ⁇ g/hr, for the treatment period, usually about 12 hours to 7 days.
  • a 20 cm 2 system would require a pergolide flux through skin of 7.5 ⁇ g/cm 2 ⁇ hr in order to achieve the desired therapeutic rate of 150 ⁇ g/hr.
  • Such a system would deliver approximately 3.6 mg of pergolide over a 24 hour period.
  • the length of time of pergolide presence and the total amount of pergolide in the plasma can be changed following the teachings of this invention to provide different treatment regimens. Thus, they can be controlled by the amount of time during which exogenous pergolide is delivered transdermally to an individual or animal.
  • the drug/permeation enhancer reservoirs were prepared by mixing ethylene vinyl acetate having a vinyl acetate content of 40 percent (“EVA 40”, USI Chemicals, Illinois), with pergolide base or mesylate, GML or LDEA, and mineral oil. The mixture was then dissolved in tetrahydrofuran. After blending, the mixture was hand cast and dried to a 5 mil. thick film. The composition of the drug reservoirs is shown in Table 2.
  • the film was then laminated to a pigmented medium density polyethylene/aluminum foil/PET/EVA (Medpar®) backing on one side and an acrylate contact adhesive on the opposite side (3M).
  • the laminate was then punched down to an area of 1.6 cm 2 .
  • Circular pieces of human epidermis were placed with stratum corneum facing up.
  • the release liner of the laminate was removed and the system was centered over the stratum corneum side of the epidermis.
  • the edges of epidermis were then folded around the system.
  • This assembly was then mounted on a Teflon rod.
  • a known volume of receptor solution was then placed in a test tube and was equilibrated at 35° C.
  • the Teflon rod with system and epidermis attached was then placed in a water bath at 35° C. Mixing was accomplished by attachment to a motor which caused constant vertical mixing.
  • the entire receptor solution was removed from the test tubes and replaced with an equal volume of fresh receptor solutions previously equilibrated at 35° C.
  • the drug/permeation enhancer reservoirs were prepared according to Example 2.
  • the film was then laminated to Medpar backing on one side and a polyisobutylene adhesive containing 2.5% by weight of pergolide on the other.
  • the adhesive was prepared by dissolving 19.8% 1.2M polyisobutylene, 24.7% 35K polyisobutylene and 55.5% light mineral oil in heptane.
  • the 2.5% pergolide was added and the entire mixture was cast to a dry thickness of 2 mils.
  • the film was then cut into circles using a stainless steel punch with an area of 1.6 cm 2 .
  • the epidermis was separated from the dermis of the skin donor after immersion in 60° C. water for 60 seconds. Discs (7 ⁇ 8-inch diameter) were cut from the epidermis, and the discs were kept at 4° C. in a hydrated state until they were used.
  • the release liner was removed and the drug-releasing surface was placed against the stratum corneum side of a disc of epidermis which had been blotted dry just prior to use.
  • the excess epidermis was wrapped around the device so that none of the device edge was exposed to the receptor solution.
  • the device covered with epidermis was attached to the flat side of the Teflon holder of a release rate rod using nylon netting and nickel wire.
  • the rods were reciprocated in a fixed volume of receptor solution.
  • the entire receptor solution was changed at each sampling time.
  • the temperature of the receptor solution in the water bath was maintained at 35° C.
  • the cumulative release of the pergolide base or pergolide mesylate is shown in FIGS. 9 and 10.
  • the drug/permeation enhancer reservoirs were prepared by mixing pergolide base or mesylate, EtOH, GML, and caproyl lactic acid (CLA) as shown in Table 3.
  • a desired quantity of the mixture as formed in Example 4 was then applied on the surface of a previously formed trilaminate consisting of a 2 mil thick ethylene vinyl acetate film having a vinyl acetate content of 28% for use as a rate controlling membrane; a polyisobutylene contact adhesive containing 2.5% by weight pergolide; and a polyethylene ethylene terephthalate film coated with fluorocarbon for use as a release liner.
  • a Medpar backing was then applied on top of the mixture and the entire system was heat sealed. The systems were then die-cut to the required sizes for use in the in vitro test method described in Examples 2-4.
  • the cumulative release of the pergolide base and mesylate are shown in FIGS. 13 and 14.
  • the skin flux of the base and mesylate are shown in FIGS. 15 and 16.
  • the drug/permeation enhancer reservoirs were prepared by mixing ethylene vinyl acetate having a vinyl acetate content of 40 percent (“EVA 40”, USI Chemicals, Illinois), pergolide mesylate, GML, Laureth-4 (L-4), and an optional amount of mineral oil. The mixture was then dissolved in tetrahydrofuran. After blending, the mixture was hand cast and dried to a 5 mil. thick film. The composition of the drug reservoir is shown in Table 4.
  • the film was then laminated to a Medpar backing on one side.
  • a polyisobutylene adhesive, 3M, or no adhesive was applied on the other side of the film.
  • the systems were then die-cut to the required sizes for use in the in vitro test method described in Examples 2-4.
  • the skin flux of the mesylate is shown in FIGS. 17 and 18.
  • the cumulative release of the mesylate is shown in FIGS. 19 and 20.

Landscapes

  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dermatology (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Psychology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
US08/473,631 1995-06-07 1995-06-07 Formulations for transdermal delivery of pergolide Expired - Lifetime US6572879B1 (en)

Priority Applications (18)

Application Number Priority Date Filing Date Title
US08/473,631 US6572879B1 (en) 1995-06-07 1995-06-07 Formulations for transdermal delivery of pergolide
DK95929346T DK0831827T3 (da) 1995-06-07 1996-06-07 Nye formuleringer til transdermal levering af pergolid
AU64764/96A AU6476496A (en) 1995-06-07 1996-06-07 Novel formulations for transdermal delivery of pergolide
ES95929346T ES2285704T3 (es) 1995-06-07 1996-06-07 Formulaciones nuevas para la administracion transdermica de pergolida.
DE19681435T DE19681435T1 (de) 1995-06-07 1996-06-07 Neue Formulierungen zur transdermalen Abgabe von Pergolid
EP95929346A EP0831827B1 (de) 1995-06-07 1996-06-07 Neue formulierungen zur transdermalen verabreichung von pergolid
JP9501953A JPH11507361A (ja) 1995-06-07 1996-06-07 ペルゴライドの経皮放出用新規製剤
EP04075596A EP1428527A1 (de) 1995-06-07 1996-06-07 Neue Zusammensetzungen zur transdermalen Verabrechung von Pergolid
PCT/US1996/009692 WO1996040139A1 (en) 1995-06-07 1996-06-07 Novel formulations for transdermal delivery of pergolide
GB9724267A GB2316004B (en) 1995-06-07 1996-06-07 Novel formulations for transdermal delivery of pergolide
AT95929346T ATE361073T1 (de) 1995-06-07 1996-06-07 Neue formulierungen zur transdermalen verabreichung von pergolid
PT95929346T PT831827E (pt) 1995-06-07 1996-06-07 Novas formulações para administração trasdérmica de pergolide
CA002221263A CA2221263A1 (en) 1995-06-07 1996-06-07 Novel formulations for transdermal delivery of pergolide
DE69637061T DE69637061T2 (de) 1995-06-07 1996-06-07 Zusammensetzung und Vorrichtung zur Verabreichung von Pergolid in einer therapeutisch wirksamen Rate
US08/768,600 US6001390A (en) 1995-06-07 1996-12-18 Formulations for transdermal delivery of pergolide
MXPA/A/1997/009872A MXPA97009872A (es) 1995-06-07 1997-12-08 Formulaciones novedosas para suministrotransderico de pergolide
US10/121,478 US20040209909A1 (en) 1995-06-07 2002-04-09 Novel formulations for transdermal delivery of pergolide
JP2007168802A JP2007238636A (ja) 1995-06-07 2007-06-27 ペルゴライドの経皮放出用新規製剤

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US08/473,631 US6572879B1 (en) 1995-06-07 1995-06-07 Formulations for transdermal delivery of pergolide

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US08/768,600 Continuation-In-Part US6001390A (en) 1995-06-07 1996-12-18 Formulations for transdermal delivery of pergolide
US31765399A Continuation 1995-06-07 1999-05-24

Publications (1)

Publication Number Publication Date
US6572879B1 true US6572879B1 (en) 2003-06-03

Family

ID=23880356

Family Applications (3)

Application Number Title Priority Date Filing Date
US08/473,631 Expired - Lifetime US6572879B1 (en) 1995-06-07 1995-06-07 Formulations for transdermal delivery of pergolide
US08/768,600 Expired - Lifetime US6001390A (en) 1995-06-07 1996-12-18 Formulations for transdermal delivery of pergolide
US10/121,478 Abandoned US20040209909A1 (en) 1995-06-07 2002-04-09 Novel formulations for transdermal delivery of pergolide

Family Applications After (2)

Application Number Title Priority Date Filing Date
US08/768,600 Expired - Lifetime US6001390A (en) 1995-06-07 1996-12-18 Formulations for transdermal delivery of pergolide
US10/121,478 Abandoned US20040209909A1 (en) 1995-06-07 2002-04-09 Novel formulations for transdermal delivery of pergolide

Country Status (12)

Country Link
US (3) US6572879B1 (de)
EP (2) EP0831827B1 (de)
JP (2) JPH11507361A (de)
AT (1) ATE361073T1 (de)
AU (1) AU6476496A (de)
CA (1) CA2221263A1 (de)
DE (2) DE19681435T1 (de)
DK (1) DK0831827T3 (de)
ES (1) ES2285704T3 (de)
GB (1) GB2316004B (de)
PT (1) PT831827E (de)
WO (1) WO1996040139A1 (de)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040028723A1 (en) * 2000-08-24 2004-02-12 Reinhard Horowski Transdermal therapeutic system for treating restless-legs-syndrome
US20040219191A1 (en) * 2000-12-16 2004-11-04 Karsten Kuhn Use of a dopamine agonist with a short half-life for treating illnesses which can be treated by dopaminergic means
US20050181037A1 (en) * 2002-05-24 2005-08-18 Neopharm, Inc. Cardiolipin compositions their methods of preparation and use
US20050191338A1 (en) * 2004-01-30 2005-09-01 Lifeng Kang Transdermal drug delivery composition comprising a small molecule gel and process for the preparation thereof
US20050214353A1 (en) * 2000-10-20 2005-09-29 Reinhard Horowski Transdermal therapeutic system
US20050260255A1 (en) * 2002-08-28 2005-11-24 Takaaki Terahara Adhesive patch
US20050266068A1 (en) * 2002-05-24 2005-12-01 Neopharm, Inc. Cardiolipin molecules and methods of synthesis
US20050277611A1 (en) * 2002-10-16 2005-12-15 Neopharm, Inc. Cationic cardiolipin analoges and its use thereof
US20060110433A1 (en) * 2002-08-28 2006-05-25 Takaaki Terahara Adhesive patch
US20090169601A1 (en) * 2005-10-21 2009-07-02 Lts Lohmann Therapie-Systeme Ag Transdermal Therapeutic System for Administering Lipophilic and/or Sparingly Skin- Permeable Active Substances
US9072682B2 (en) 2012-12-31 2015-07-07 Mylan Inc. Transdermal dosage form for low-melting point active agent

Families Citing this family (46)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6572879B1 (en) * 1995-06-07 2003-06-03 Alza Corporation Formulations for transdermal delivery of pergolide
DE19626621A1 (de) * 1996-07-02 1998-01-08 Hexal Ag Pflaster zur transdermalen Anwendung von Pergolid
US6623752B1 (en) 1996-07-02 2003-09-23 Hexal Ag Patch for transdermal application for pergolid
CA2264687C (en) * 1996-10-24 2006-04-25 Alza Corporation Permeation enhancers for transdermal drug delivery compositions, devices, and methods
DE19821788C1 (de) * 1998-05-15 1999-12-02 Sanol Arznei Schwarz Gmbh Transdermales Therapeutisches System (TTS) Pergolid enthaltend
US7258869B1 (en) 1999-02-08 2007-08-21 Alza Corporation Stable non-aqueous single phase viscous vehicles and formulations utilizing such vehicle
CA2361424C (en) † 1999-02-08 2009-04-28 Intarcia Therapeutics, Inc. Stable non-aqueous single phase viscous vehicles and formulations utilizing such vehicles
US20070148228A1 (en) * 1999-02-22 2007-06-28 Merrion Research I Limited Solid oral dosage form containing an enhancer
US7658938B2 (en) * 1999-02-22 2010-02-09 Merrion Reasearch III Limited Solid oral dosage form containing an enhancer
US8119159B2 (en) * 1999-02-22 2012-02-21 Merrion Research Iii Limited Solid oral dosage form containing an enhancer
DE10341317B4 (de) * 2003-09-03 2008-10-23 Axxonis Pharma Ag Transdermales therapeutisches System (TTS) zur Verabreichung von Ergolinverbindungen ausgenommen Pergolid
GB0026137D0 (en) * 2000-10-25 2000-12-13 Euro Celtique Sa Transdermal dosage form
DE10110953A1 (de) * 2001-03-07 2002-09-19 Lohmann Therapie Syst Lts Transdermales therapeutisches System zur Verabreichung von partiellen Dopamin-D2-Agonisten
JP2005506297A (ja) * 2001-03-30 2005-03-03 エラン ファーマシューティカルズ インコーポレイテッド ペルゴリドの経皮送達
FR2823999B1 (fr) * 2001-04-27 2003-06-27 Commissariat Energie Atomique Dispositif miniature de separation et d'isolement d'objets biologiques et utilisations
EP1392272B1 (de) 2001-05-11 2014-08-06 Merrion Research III Limited Permeationsverbesserer
US20040120995A1 (en) * 2002-04-01 2004-06-24 Martin Debra A Transdermal delivery of pergolide
US7731947B2 (en) 2003-11-17 2010-06-08 Intarcia Therapeutics, Inc. Composition and dosage form comprising an interferon particle formulation and suspending vehicle
DE602004026173D1 (de) * 2003-04-29 2010-05-06 Gen Hospital Corp Verfahren und vorrichtungen für die verzögerte freisetzung von mehreren arzneimitteln
TW200514582A (en) * 2003-10-31 2005-05-01 Hisamitsu Pharmaceutical Co Transdermal preparation and method for reducing side effect in pergolide therapy
WO2006083761A2 (en) 2005-02-03 2006-08-10 Alza Corporation Solvent/polymer solutions as suspension vehicles
US11246913B2 (en) 2005-02-03 2022-02-15 Intarcia Therapeutics, Inc. Suspension formulation comprising an insulinotropic peptide
BRPI0710503A2 (pt) * 2006-04-07 2011-08-16 Merrion Res Iii Ltd uso de uma composição farmacêutica, composição farmacêutica, e, forma de dosagem oral
KR101106510B1 (ko) 2006-05-30 2012-01-20 인타르시아 세라퓨틱스 인코포레이티드 투피스, 내부채널 삼투압 전달 시스템 유동 조절기
JP2009539862A (ja) * 2006-06-09 2009-11-19 メリオン リサーチ Ｉｉｉ リミテッド 強化剤を含む固体経口投与剤形
EP2359808B1 (de) 2006-08-09 2013-05-22 Intarcia Therapeutics, Inc Osmotisches Verabreichungssystem mit Kolbenanordnung
SA08290041B1 (ar) 2007-02-01 2012-06-05 فيرينج انترناشونال سنتر اس آيه أدوية من أجل معالجة بطانة الرحم
GB2450533A (en) * 2007-06-29 2008-12-31 Ferring Int Ct Sa Treatment and prevention of endometriosis using dopamine agonists.
WO2008133908A2 (en) 2007-04-23 2008-11-06 Intarcia Therapeutics, Inc. Suspension formulations of insulinotropic peptides and uses thereof
CA2726861C (en) 2008-02-13 2014-05-27 Intarcia Therapeutics, Inc. Devices, formulations, and methods for delivery of multiple beneficial agents
RU2517135C2 (ru) 2008-05-07 2014-05-27 Меррион Рисерч Iii Лимитед Композиции пептидов и способы их получения
US20130274352A1 (en) * 2009-04-14 2013-10-17 The Regents Of The University Of California Oral Drug Devices and Drug Formulations
RU2547990C2 (ru) 2009-09-28 2015-04-10 Интарсия Терапьютикс, Инк. Быстрое достижение и/или прекращение существенной стабильной доставки лекарственного средства
US9089484B2 (en) 2010-03-26 2015-07-28 Merrion Research Iii Limited Pharmaceutical compositions of selective factor Xa inhibitors for oral administration
KR20140026354A (ko) 2011-01-07 2014-03-05 메리온 리서치 Ⅲ 리미티드 경구 투여용 철의 제약 조성물
US20120208755A1 (en) 2011-02-16 2012-08-16 Intarcia Therapeutics, Inc. Compositions, Devices and Methods of Use Thereof for the Treatment of Cancers
WO2016046150A1 (en) 2014-09-25 2016-03-31 Boehringer Ingelheim Vetmedica Gmbh Combination treatment of sglt2 inhibitors and dopamine agonists for preventing metabolic disorders in equine animals
US9889085B1 (en) 2014-09-30 2018-02-13 Intarcia Therapeutics, Inc. Therapeutic methods for the treatment of diabetes and related conditions for patients with high baseline HbA1c
JP7211704B2 (ja) 2015-01-29 2023-01-24 ノヴォ ノルディスク アー／エス Ｇｌｐ－１アゴニスト及び腸溶コーティングを含む錠剤
RU2730996C2 (ru) 2015-06-03 2020-08-26 Интарсия Терапьютикс, Инк. Системы установки и извлечения имплантата
KR102574993B1 (ko) 2016-05-16 2023-09-06 인타르시아 세라퓨틱스 인코포레이티드 글루카곤-수용체 선택적 폴리펩티드 및 이들의 이용 방법
USD840030S1 (en) 2016-06-02 2019-02-05 Intarcia Therapeutics, Inc. Implant placement guide
USD860451S1 (en) 2016-06-02 2019-09-17 Intarcia Therapeutics, Inc. Implant removal tool
JP7286542B2 (ja) 2017-01-03 2023-06-05 インターシア セラピューティクス，インコーポレイティド Ｇｌｐ－１受容体アゴニストの持続的投与及び薬物の同時投与を含む方法
US20190374534A1 (en) 2018-06-08 2019-12-12 Boehringer Ingelheim Vetmedica Gmbh Liquid pharmaceutical compositions comprising pergolide
US20240390257A1 (en) * 2023-05-27 2024-11-28 Sacheu Beauty Inc. Peel-off lip liner stain

Citations (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3598123A (en) 1969-04-01 1971-08-10 Alza Corp Bandage for administering drugs
US3598122A (en) 1969-04-01 1971-08-10 Alza Corp Bandage for administering drugs
US3731683A (en) 1971-06-04 1973-05-08 Alza Corp Bandage for the controlled metering of topical drugs to the skin
US3797494A (en) 1969-04-01 1974-03-19 Alza Corp Bandage for the administration of drug by controlled metering through microporous materials
US4031894A (en) 1975-12-08 1977-06-28 Alza Corporation Bandage for transdermally administering scopolamine to prevent nausea
US4144317A (en) 1975-05-30 1979-03-13 Alza Corporation Device consisting of copolymer having acetoxy groups for delivering drugs
US4166182A (en) 1978-02-08 1979-08-28 Eli Lilly And Company 6-n-propyl-8-methoxymethyl or methylmercaptomethylergolines and related compounds
US4201211A (en) 1977-07-12 1980-05-06 Alza Corporation Therapeutic system for administering clonidine transdermally
US4286592A (en) 1980-02-04 1981-09-01 Alza Corporation Therapeutic system for administering drugs to the skin
US4314557A (en) 1980-05-19 1982-02-09 Alza Corporation Dissolution controlled active agent dispenser
US4379454A (en) 1981-02-17 1983-04-12 Alza Corporation Dosage for coadministering drug and percutaneous absorption enhancer
US4435180A (en) 1982-05-25 1984-03-06 Alza Corporation Elastomeric active agent delivery system and method of use
US4559222A (en) 1983-05-04 1985-12-17 Alza Corporation Matrix composition for transdermal therapeutic system
US4568343A (en) 1984-10-09 1986-02-04 Alza Corporation Skin permeation enhancer compositions
US4573995A (en) 1984-10-09 1986-03-04 Alza Corporation Transdermal therapeutic systems for the administration of naloxone, naltrexone and nalbuphine
US4588580A (en) 1984-07-23 1986-05-13 Alza Corporation Transdermal administration of fentanyl and device therefor
US4645502A (en) 1985-05-03 1987-02-24 Alza Corporation Transdermal delivery of highly ionized fat insoluble drugs
US4704282A (en) 1984-06-29 1987-11-03 Alza Corporation Transdermal therapeutic system having improved delivery characteristics
US4764379A (en) 1987-08-24 1988-08-16 Alza Corporation Transdermal drug delivery device with dual permeation enhancers
EP0279986A1 (de) 1987-02-26 1988-08-31 Alza Corporation Glycerolmonolaurate enthaltende, die Hautpermeabilität vergrössernde Zusammensetzungen
US4788062A (en) 1987-02-26 1988-11-29 Alza Corporation Transdermal administration of progesterone, estradiol esters, and mixtures thereof
US4797405A (en) 1987-10-26 1989-01-10 Eli Lilly And Company Stabilized pergolide compositions
US4800204A (en) 1987-05-07 1989-01-24 Mueller Peter S Method of controlling tobacco use
US4816258A (en) 1987-02-26 1989-03-28 Alza Corporation Transdermal contraceptive formulations
US4849226A (en) 1981-06-29 1989-07-18 Alza Corporation Method for increasing oxygen supply by administering vasodilator
US4908027A (en) 1986-09-12 1990-03-13 Alza Corporation Subsaturated transdermal therapeutic system having improved release characteristics
US4935429A (en) 1985-10-25 1990-06-19 Dackis Charles A Method of treating psychostimulant addiction
US4943435A (en) 1987-10-05 1990-07-24 Pharmetrix Corporation Prolonged activity nicotine patch
US5004610A (en) 1988-06-14 1991-04-02 Alza Corporation Subsaturated nicotine transdermal therapeutic system
US5063234A (en) 1990-05-25 1991-11-05 Eli Lilly And Company Method of inhibiting demineralization of bone
DE4240798A1 (en) 1991-12-03 1993-06-09 Poli Industria Chimica S.P.A., Mailand/Milano, It Neuro-protective agents preventing nerve damage - contain ergot derivs. e.g. clavine lysergic acid amide or 8-alpha-amino:ergoline derivs.
US5229129A (en) 1989-07-12 1993-07-20 Cygnus Therapeutic Systems Transdermal administration of lisuride
EP0559411A1 (de) 1992-03-04 1993-09-08 Eli Lilly And Company System und Methode zur einstellbaren Verabreichung von therapeutischen Stoffen aus transdermalen Pflastern
US5252335A (en) 1989-07-12 1993-10-12 Cygnus Therapeutic Systems Transdermal administration of lisuride
US5314694A (en) 1990-10-29 1994-05-24 Alza Corporation Transdermal formulations, methods and devices
US5378730A (en) * 1988-06-09 1995-01-03 Alza Corporation Permeation enhancer comprising ethanol and monoglycerides
US5446070A (en) * 1991-02-27 1995-08-29 Nover Pharmaceuticals, Inc. Compositions and methods for topical administration of pharmaceutically active agents
US5607691A (en) 1992-06-12 1997-03-04 Affymax Technologies N.V. Compositions and methods for enhanced drug delivery

Family Cites Families (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0240044B2 (ja) * 1978-02-08 1990-09-10 Lilly Co Eli Paakinsonshokogunchiryozai
JPH0240647B2 (ja) * 1978-02-08 1990-09-12 Lilly Co Eli Purorakuchinbunpyokuseizai
US4675322A (en) * 1984-12-10 1987-06-23 Eli Lilly And Company 1-Substituted-6-n-propyl-8β-methylthio-methylergolines
US4782152A (en) * 1985-08-16 1988-11-01 Eli Lilly And Company Decyanation of pergolide intermediate
US4814168A (en) * 1988-03-04 1989-03-21 Noven Pharmaceuticals, Inc. Transdermal multipolymer drug delivery system
US4973468A (en) * 1989-03-22 1990-11-27 Cygnus Research Corporation Skin permeation enhancer compositions
US5114948A (en) * 1989-10-19 1992-05-19 Eli Lilly And Company Stabilized pergolide compositions
JP3255717B2 (ja) * 1991-08-08 2002-02-12 積水化学工業株式会社 経皮吸収製剤
JPH05271658A (ja) * 1992-03-27 1993-10-19 Chisso Corp 反強誘電性液晶組成物
DE69326461T2 (de) * 1992-06-11 2000-05-04 Theratech Inc., Salt Lake City Verwendung von glyzerin zur dämpfung der transdermalen arzneimittelverabreichung
US5919478A (en) * 1993-06-25 1999-07-06 Alza Corporation Incorporating poly-N-vinyl amide in a transdermal system
JP3021661B2 (ja) * 1994-03-07 2000-03-15 セラテック・インコーポレーテッド 薬剤含有接着複合体の経皮放出デバイス
US6572879B1 (en) * 1995-06-07 2003-06-03 Alza Corporation Formulations for transdermal delivery of pergolide

Patent Citations (41)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3598122B1 (de) 1969-04-01 1982-11-23
US3598122A (en) 1969-04-01 1971-08-10 Alza Corp Bandage for administering drugs
US3797494A (en) 1969-04-01 1974-03-19 Alza Corp Bandage for the administration of drug by controlled metering through microporous materials
US3598123A (en) 1969-04-01 1971-08-10 Alza Corp Bandage for administering drugs
US3731683A (en) 1971-06-04 1973-05-08 Alza Corp Bandage for the controlled metering of topical drugs to the skin
US4144317A (en) 1975-05-30 1979-03-13 Alza Corporation Device consisting of copolymer having acetoxy groups for delivering drugs
US4031894A (en) 1975-12-08 1977-06-28 Alza Corporation Bandage for transdermally administering scopolamine to prevent nausea
US4201211A (en) 1977-07-12 1980-05-06 Alza Corporation Therapeutic system for administering clonidine transdermally
US4166182A (en) 1978-02-08 1979-08-28 Eli Lilly And Company 6-n-propyl-8-methoxymethyl or methylmercaptomethylergolines and related compounds
US4286592A (en) 1980-02-04 1981-09-01 Alza Corporation Therapeutic system for administering drugs to the skin
US4314557A (en) 1980-05-19 1982-02-09 Alza Corporation Dissolution controlled active agent dispenser
US4379454A (en) 1981-02-17 1983-04-12 Alza Corporation Dosage for coadministering drug and percutaneous absorption enhancer
US4849226A (en) 1981-06-29 1989-07-18 Alza Corporation Method for increasing oxygen supply by administering vasodilator
US4435180A (en) 1982-05-25 1984-03-06 Alza Corporation Elastomeric active agent delivery system and method of use
US4559222A (en) 1983-05-04 1985-12-17 Alza Corporation Matrix composition for transdermal therapeutic system
US4704282A (en) 1984-06-29 1987-11-03 Alza Corporation Transdermal therapeutic system having improved delivery characteristics
US4588580A (en) 1984-07-23 1986-05-13 Alza Corporation Transdermal administration of fentanyl and device therefor
US4588580B2 (en) 1984-07-23 1999-02-16 Alaz Corp Transdermal administration of fentanyl and device therefor
US4588580B1 (de) 1984-07-23 1989-01-03
US4568343A (en) 1984-10-09 1986-02-04 Alza Corporation Skin permeation enhancer compositions
US4573995A (en) 1984-10-09 1986-03-04 Alza Corporation Transdermal therapeutic systems for the administration of naloxone, naltrexone and nalbuphine
US4645502A (en) 1985-05-03 1987-02-24 Alza Corporation Transdermal delivery of highly ionized fat insoluble drugs
US4935429A (en) 1985-10-25 1990-06-19 Dackis Charles A Method of treating psychostimulant addiction
US4908027A (en) 1986-09-12 1990-03-13 Alza Corporation Subsaturated transdermal therapeutic system having improved release characteristics
EP0279986A1 (de) 1987-02-26 1988-08-31 Alza Corporation Glycerolmonolaurate enthaltende, die Hautpermeabilität vergrössernde Zusammensetzungen
US4816258A (en) 1987-02-26 1989-03-28 Alza Corporation Transdermal contraceptive formulations
US4788062A (en) 1987-02-26 1988-11-29 Alza Corporation Transdermal administration of progesterone, estradiol esters, and mixtures thereof
US4800204A (en) 1987-05-07 1989-01-24 Mueller Peter S Method of controlling tobacco use
US4764379A (en) 1987-08-24 1988-08-16 Alza Corporation Transdermal drug delivery device with dual permeation enhancers
US4943435A (en) 1987-10-05 1990-07-24 Pharmetrix Corporation Prolonged activity nicotine patch
US4797405A (en) 1987-10-26 1989-01-10 Eli Lilly And Company Stabilized pergolide compositions
US5378730A (en) * 1988-06-09 1995-01-03 Alza Corporation Permeation enhancer comprising ethanol and monoglycerides
US5004610A (en) 1988-06-14 1991-04-02 Alza Corporation Subsaturated nicotine transdermal therapeutic system
US5229129A (en) 1989-07-12 1993-07-20 Cygnus Therapeutic Systems Transdermal administration of lisuride
US5252335A (en) 1989-07-12 1993-10-12 Cygnus Therapeutic Systems Transdermal administration of lisuride
US5063234A (en) 1990-05-25 1991-11-05 Eli Lilly And Company Method of inhibiting demineralization of bone
US5314694A (en) 1990-10-29 1994-05-24 Alza Corporation Transdermal formulations, methods and devices
US5446070A (en) * 1991-02-27 1995-08-29 Nover Pharmaceuticals, Inc. Compositions and methods for topical administration of pharmaceutically active agents
DE4240798A1 (en) 1991-12-03 1993-06-09 Poli Industria Chimica S.P.A., Mailand/Milano, It Neuro-protective agents preventing nerve damage - contain ergot derivs. e.g. clavine lysergic acid amide or 8-alpha-amino:ergoline derivs.
EP0559411A1 (de) 1992-03-04 1993-09-08 Eli Lilly And Company System und Methode zur einstellbaren Verabreichung von therapeutischen Stoffen aus transdermalen Pflastern
US5607691A (en) 1992-06-12 1997-03-04 Affymax Technologies N.V. Compositions and methods for enhanced drug delivery

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040101550A1 (en) * 2000-08-24 2004-05-27 Fred Windt-Hanke Transdermal therapeutic system
US20040028723A1 (en) * 2000-08-24 2004-02-12 Reinhard Horowski Transdermal therapeutic system for treating restless-legs-syndrome
US20050220855A1 (en) * 2000-08-24 2005-10-06 Reinhard Horowski Transdermal therapeutic system
US20050214353A1 (en) * 2000-10-20 2005-09-29 Reinhard Horowski Transdermal therapeutic system
US7258871B2 (en) 2000-10-20 2007-08-21 Neurobiotec Gmbh Combination of a transdermal therapeutic system and an oral and/or parenteral preparation containing dopamine agonists for the treatment of dopaminergic disease states
US20040219191A1 (en) * 2000-12-16 2004-11-04 Karsten Kuhn Use of a dopamine agonist with a short half-life for treating illnesses which can be treated by dopaminergic means
US20050181037A1 (en) * 2002-05-24 2005-08-18 Neopharm, Inc. Cardiolipin compositions their methods of preparation and use
US20050266068A1 (en) * 2002-05-24 2005-12-01 Neopharm, Inc. Cardiolipin molecules and methods of synthesis
US8691267B2 (en) 2002-08-28 2014-04-08 Hisamitsu Pharmaceutical Co., Inc. Adhesive patch
US20050260255A1 (en) * 2002-08-28 2005-11-24 Takaaki Terahara Adhesive patch
US20060110433A1 (en) * 2002-08-28 2006-05-25 Takaaki Terahara Adhesive patch
US20050277611A1 (en) * 2002-10-16 2005-12-15 Neopharm, Inc. Cationic cardiolipin analoges and its use thereof
US20050191338A1 (en) * 2004-01-30 2005-09-01 Lifeng Kang Transdermal drug delivery composition comprising a small molecule gel and process for the preparation thereof
US8309120B2 (en) * 2005-10-21 2012-11-13 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system for administering lipophilic and/or sparingly skin- permeable active substances
US20120316520A1 (en) * 2005-10-21 2012-12-13 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system for administering lipophilic and/or sparingly skin-permeable active substances
US20090169601A1 (en) * 2005-10-21 2009-07-02 Lts Lohmann Therapie-Systeme Ag Transdermal Therapeutic System for Administering Lipophilic and/or Sparingly Skin- Permeable Active Substances
US9486417B2 (en) * 2005-10-21 2016-11-08 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system for administering lipophilic and/or sparingly skin-permeable active substances
US9072682B2 (en) 2012-12-31 2015-07-07 Mylan Inc. Transdermal dosage form for low-melting point active agent
US9452145B2 (en) 2012-12-31 2016-09-27 Mylan Inc Transdermal dosage form for low-melting point active agent

Also Published As

Publication number Publication date
GB9724267D0 (en) 1998-01-14
ES2285704T3 (es) 2007-11-16
DE69637061T2 (de) 2008-01-10
EP1428527A1 (de) 2004-06-16
DK0831827T3 (da) 2007-09-10
EP0831827B1 (de) 2007-05-02
AU6476496A (en) 1996-12-30
GB2316004A (en) 1998-02-18
JP2007238636A (ja) 2007-09-20
ATE361073T1 (de) 2007-05-15
DE69637061D1 (de) 2007-06-14
EP0831827A1 (de) 1998-04-01
JPH11507361A (ja) 1999-06-29
US20040209909A1 (en) 2004-10-21
US6001390A (en) 1999-12-14
DE19681435T1 (de) 1998-07-23
CA2221263A1 (en) 1996-12-19
MX9709872A (es) 1998-08-30
WO1996040139A1 (en) 1996-12-19
PT831827E (pt) 2007-07-20
GB2316004B (en) 1999-08-04

Similar Documents

Publication Publication Date Title
US6572879B1 (en) Formulations for transdermal delivery of pergolide
US6512010B1 (en) Formulations for the administration of fluoxetine
AU679794B2 (en) Monoglyceride/lactate ester permeation enhancer for oxybutynin
US5508039A (en) Controlled transdermal administration of melatonin
EP0946184B1 (de) Neue formulierungen zur transdermale verabreichung von fluoxetinacetat und fluoxetinmaleat
US5900250A (en) Monoglyceride/lactate ester permeation enhancer for oxybutnin
WO1994021262A1 (en) Device for the transdermal administration of alprazolam
US6699497B1 (en) Formulations for the transdermal administration of fenoldopam
US20010051181A1 (en) Novel formulations for the transdermal administration of asimadoline
EP1100476B1 (de) Formulierungen zur transdermalen verabreichung von fenoldopam
EP1393724B1 (de) Neue Formulierungen zur transdermale Verabreichung von Fluoxetin
EP1216036B1 (de) Transdermale verabreichung von n-(2,5 disubstituierten phenyl)-n'-(3 substituierten phenyl)-n'-methyl guanidinen
WO1999032096A1 (en) Novel formulations for the transdermal administration of asimadoline
HK1063148B (en) Novel formulations for the transdermal administration of fluoxetine
HK1036594B (en) Formulations for the transdermal administration of fenoldopam
US20040258742A1 (en) Transdermal administration of N-(2,5-disubstituted phenyl)-N'-(3-substituted phenyl)-N'-methyl guanidines
MXPA97009872A (es) Formulaciones novedosas para suministrotransderico de pergolide

Legal Events

Date Code Title Description
AS Assignment

Owner name: ALZA CORPORATION, CALIFORNIA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:YUM, SU IL;NELSON, MELINDA K.;CAMPBELL, PATRICIA S.;REEL/FRAME:007556/0624;SIGNING DATES FROM 19950602 TO 19950714

AS Assignment

Owner name: ALZA CORPORATION, CALIFORNIA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:YUM, SU IL;NELSON, MELINDA K.;CAMPBELL, PATRICIA S.;REEL/FRAME:007582/0894;SIGNING DATES FROM 19950602 TO 19950714

STCF Information on status: patent grant

Free format text: PATENTED CASE

FPAY Fee payment

Year of fee payment: 4

FPAY Fee payment

Year of fee payment: 8

FPAY Fee payment

Year of fee payment: 12